More than 1.2 million people in the United States are living with human immunodeficiency virus (HIV). Alcohol abuse is also prevalent in the US with more than sixty percent of the population reporting consuming alcohol over the past year. Since people who abuse drugs and alcohol are at risk for HIV infection, there is a comorbidity between alcohol and HIV which represents a unique population that warrants investigation. Therefore, studying the effects of alcohol during HIV infection is necessary to find treatments that account for both diseases. Both alcohol and HIV activate microglia, the resident phagocytic cells of the central nervous system (CMS). Alcohol causes oxidative stress in microglia whereas HIV uses microglia as a vehicle for replication, and the resulting microglia infection produces neurotoxins and excitotoxins. The combined effects of alcohol and HIV or HIV-glycoproteins (HIV-gp120) on microglia have not been studied. The proposed experiments will examine microglia in vitro to determine the extent to which acute and chronic alcohol impacts HIV replication and the cellular toxicity of HIV-gp120. The experiments will evaluate cell death and oxidative damage. In addition, we will use antioxidant expressing gene delivery vectors to elucidate the pathways involved and provide potential therapeutics. The second portion of the proposed experiments will utilize an in vivo rat model of chronic CMS injury induced by expression of HIV-gp120 using SV40 gene delivery vectors (SV(gp120)) to model the long-term effects of HIV encephalitis. The animals will be treated with chronic ethanol which, followed by an intracranial injection of SV(gp120) to determine the extent to which alcohol impacts the progression of HIV-induced CMS injury. The proposed research will elucidate the interation of alcohol and HIV in vitro and in vivo to provide a foundation for potential therapeutics. Public Health Relevance: The impact that alcohol abuse has on patients with HIV is not well understood. HIV and alcohol abuse, individually, are detrimental to brain function and the combination presents a public health problem. My research focuses on finding the cause of this problem and potential treatments both at the level of the immune cells of the brain and in animals.